S263: CYTOPENIAS, AGE AND CAR-HEMATOTOX SCORE PREDICT THE DEVELOPMENT OF POST CAR T-CELL THERAPY-RELATED MYELOID NEOPLASMS
Authors: Mark Gurney, Hassan Alkhateeb, Syed Shah, Radhika Bansal, Matthew Hathcock, Allison Rosenthal, Mohamed Kharfan-Dabaja, Taxiarchis Kourelis, Mrinal Patnaik, Dong Chen, Aref Al-Kali, Saad Kenderian, Yi Lin, Mithun Shah
Journal: HemaSphere (2023)

Background: Therapy-related myeloid neoplasms (t-MN) have been reported following CAR T-cell therapy for multiple myeloma (MM) and high-grade B-cell lymphoma (HGBCL). Pre-existing clonal hematopoiesis increases t-MN risk but is not routinely tested for, whereas routinely available predictive factors are not clearly defined. The CAR-HEMATOTOX score (CHS) is based upon pre-lymphodepletion (LD) cytopenias and inflammatory markers. It predicts severe neutropenia, infection risk, and survival after CAR-T cell therapy for MM and HGBCL, but its relevance to t-MN risk is unknown. Aims: To evaluate the role of pre-LD clinical and laboratory factors, including the CHS, to predict the development of post CAR-T cell t-MN. Methods: Patients (age ≥18 years) who received CAR-T cell therapy for HGBCL (CD19) or MM (BCMA) at Mayo Clinic and later developed t-MN were identified. A control cohort without a t-MN (or clonal cytopenia) diagnosis was matched 6:1 for primary diagnosis (MM/HGBCL). Thresholds for continuous predictors were identified by logistic regression, ROC curve generation, and optimization of Youden's J statistic. Univariate and multivariate Cox proportional hazards regression was used to identify factors predictive of t-MN. Multivariate models were restricted to two predictors due to cohort size and compared by concordance index (CI). CHS was calculated as previously reported (Rejeski et al. Blood 2021). Competing risks analysis was used for incidence rate estimates. Statistical testing was performed using BlueSky Statistics (v7.3). Results: Of 312 patients, 20 (6%) developed t-MN (18 t-MDS, 2 t-AML) at a median 10 months (IQR 5-18) from infusion. The overall cumulative incidence rate of t-MN at 1-, 2-, and 3- years was 4%, 6%, and 9%, respectively. Median age at t-MN diagnosis was 68 years (IQR 65-72), and 12 (60%) patients were female. Del(5q), -7/del(7q), complex and monosomal karyotype were seen in 9 (45%), 10 (50%), 8 (40%), and 7 (35%) cases respectively. TP53 mutations occurred in 9/19 (47%) cases tested (multi-hit in 6/9). Median overall survival from t-MN diagnosis was 9 months. At baseline, patients who developed t-MN were older (67 vs 61 years, p=0.01), and more likely to have CHS ≥2 (60 vs 35%, p=0.03), Figure A. Age, pre-LD hemoglobin, platelet count, and CHS ≥2 were associated with t-MN occurrence on univariate analysis. No association was observed for prior lines of therapy, prior auto-SCT, baseline CRP or ferritin. Optimal cut-offs were rounded to age ≥65, platelet count ≤140, and CH score ≥2. Multivariate cox regression identified age ≥65 (HR 4.3, p=0.01), and platelet count ≤140 (HR 3.0, p=0.01) as the best performing pair (CI 0.77, 'model 1'). Combining CHS ≥2 (HR 2.9, p=0.02) and age ≥65 (HR 4.9, p<0.01) performed similarly (CI: 0.77, 'model 2') and improved prediction relative to CHS ≥2 alone (HR 3.0, p=0.02, CI: 0.61). Applied to a consecutive cohort (n=140, 90% HGBCL) who received commercial CAR-T products (Figure B & C), stratification by model 2 (CHS ≥2 and age ≥65) resulted in t-MN rates of 7/100 person-years (PY) and 23/100 PY based upon the presence of 1 (intermediate risk, 44% of cohort) or 2 factors (high risk, 13% of cohort) respectively. No events occurred in the low-risk category (43% of cohort). Summary/Conclusion: A model incorporating CHS and age stratifies t-MN risk post CAR-T cell therapy for MM/HGBCL, with age and thrombocytopenia independently predicting t-MN risk. Clinical stratification of t-MN risk prior to CAR T-cell therapy may identify a subgroup of patients most likely to benefit from additional screening and closer surveillance.Keywords: Therapy-related AML, Hematotoxicity, CAR-T, MDS